Pleural Effusion Associated with Pegylated Interferon Alpha and Ribavirin Treatment for Chronic Hepatitis C

CASE REPORT Pleural Effusion Associated with Pegylated Interferon Alpha and Ribavirin Treatment for Chronic Hepatitis C

Amit Arora1 1 Department of Medicine, NorthShore University HealthSystem, Evanston, Illinois. 1 Leonardo Vargas 2 Division of Pulmonary and Critical Care Medicine, NorthShore University HealthSystem, Evanston, Illinois. Tomasz J. Kuzniar2

Disclosure: Nothing to report.

Lung toxicity related to interferon (IFN) alpha typically takes a form of interstitial pneumonitis, granulomatous inﬂammation, or organizing pneumonia. We report a case of a 52-year-old woman, who developed pneumonitis with exudative, lymphocytic-predominant pleural effusion following treatment with pegylated IFN alpha and ribavirin for hepatitis C. Her symptoms and lung ﬁndings resolved over 3 months of observation without corticosteroid therapy. Journal of Hospital Medicine 2009;4:E45–E46. VC 2009 Society of Hospital Medicine.

KEYWORDS: hepatitis C, interferon alpha, lung toxicity, pleural effusion, ribavirin.

Case Report There were no atypical or malignant cells. Bacterial, fungal, A 52-year-old woman with chronic hepatitis C was admitted viral, acid-fast stains and cultures, and polymerase chain with complaints of dry cough, shortness of breath, and reaction (PCR) for Mycobacterium tuberculosis were all neg- fever. Four days prior to admission, she had successfully fin- ative. An echocardiogram and plasma B-type natriuretic ished a 44-week course of pegylated interferon (IFN) alpha peptide were normal. and ribavirin with undetectable viral load on completion of Serum antinuclear and antineutrophilic cytoplasmic anti- treatment. At 30 weeks, she had developed a dry cough, bodies, Bordetella pertussis PCR, serologies for Mycoplasma, which she initially ignored. Three weeks later, as a result of Chlamydia, Coxiella, and urinary antigens for Legionella and a violent coughing episode, she sustained a spontaneous Blastomyces were all negative. Bronchoscopy with bron- uncomplicated fracture of the left sixth rib. Chest x-ray at choalveolar lavage (BAL) was performed on hospital day 5. that time did not show an infiltrate or opacity. She contin- BAL stains and cultures for bacteria, fungi, acid-fast organ- ued treatment, and over the next 6 weeks developed pro- isms, Cytomegalovirus, Herpes simplex virus, Legionella, and gressive dyspnea on exertion. Five days prior to admission, Pneumocystis were negative. Cytology revealed mild acute she had developed fever of 101F. Repeat chest x-ray inflammation with macrophage predominance and no ma- revealed a left lingular infiltrate and she was prescribed lev- lignant cells. ofloxacin. Her symptoms failed to improve and she was Repeat CT scan of the chest on day 6 showed bilateral admitted to the hospital. ground-glass infiltrates and persistent left pleural effusion On admission, she denied expectoration, sore throat, (Figure 1). In the absence of an identifiable cause, the night sweats, or rashes. She also denied tobacco use, pets at patient was diagnosed with interstitial pneumonitis and home, or recent travel outside the Midwest. Examination pleural effusion secondary to pegylated IFN alpha and riba- revealed a temperature of 99.4F and decreased breath virin. Treatment with steroids was considered, but was not sounds over the left lower chest. Chest x-ray revealed left- used due to recent successful suppression of hepatitis C. sided pleural effusion. D-dimer was negative. Computed to- She was discharged with continued close follow-up. Her mography (CT) scan of the chest showed a left lingular infil- fever gradually subsided over the next 2 weeks and her trate, right lower lobe ground-glass opacity, and a moder- cough continued to improve over the next 6 weeks. Follow- ately-sized left pleural effusion. Azithromycin, piperacillin/ up CT scan of the chest 3 months after discharge showed tazobactam, and vancomycin were empirically started. Over complete resolution of the left pleural effusion and near-re- the next 36 hours, she became increasingly tachypneic and solution of the bilateral basal infiltrates. short of breath. A diagnostic and therapeutic thoracentesis with aspiration of 800 mL of light-yellow-colored fluid Discussion brought symptomatic relief. Pleural fluid analysis revealed Use of IFN alpha has been associated with multiple forms an exudative effusion with 3.8 gm/dL of protein (serum pro- of lung toxicity, of which interstitial pneumonitis and granu- tein ¼ 6.2 gm/dL), lactic dehydrogenase (LDH) of 998 IU/L lomatous inflammation resembling sarcoidosis are the most (serum LDH ¼ 293 IU/L), and normal adenosine deaminase. common. Unusual forms include isolated nonproductive The cell count was 362 per mm3 with 37% lymphocytes, cough, exacerbation of asthma, organizing pneumonia, 32% macrophages, 26% neutrophils, and 1% eosinophils. pleural effusion, adult respiratory distress syndrome, and

2009 Society of Hospital Medicine DOI 10.1002/jhm.452 Published online in wiley InterScience (www.interscience.wiley.com).

Journal of Hospital Medicine Vol 4 No 7 September 2009 E45 BAL fluid cytology in our patient revealed predominant macrophages. Yamaguchi et al., in their analysis of BAL fluid in patients with hepatitis C, demonstrated increased macrophages (76% and 77.5%) and lymphocytes (19.8% and 18.8%) before and after treatment with IFN alpha, respectively. The cornerstone of management of lung toxicity due to IFN is to diminish or stop use of the offending agent. Our patient demonstrated complete recovery of symptoms and radiological resolution within 3 months of completion of IFN therapy, without corticosteroid therapy. Although corticosteroid regimes of 6 to 12 months have been used to manage IFN related lung toxicity, most patients recover without them.6 Moreover, corticosteroids have been impli- cated in the recurrence of hepatitis C. We believe that our patient’s pathology is most consistent with lung and pleural toxicity temporally related to IFN treatment. Through our case report, we bring to attention FIGURE 1. Repeat CT scan of the chest on day 6 showed this infrequent complication, and emphasize its self-limited bilateral ground-glass infiltrates and persistent left pleural course upon withdrawal of the offending agent. effusion. Acknowledgements exacerbation of vasculitis.1 Reports of adverse pulmonary The authors thank Dr. Philippe Camus, Hoˆpital Le Bocage, Dijon, effects of ribavirin are sparse, and it has not been impli- France, for his invaluable suggestions and for reviewing this case report prior to submission. cated as a sole etiologic agent in causing lung toxicity. It is therefore likely that pulmonary toxicity observed in patients Address for correspondence and reprint requests: with hepatitis C virus (HCV) infection undergoing IFN alpha Tomasz J. Kuzniar, MD, PhD, Division of Pulmonary and Critical and ribavirin therapy is due to the IFN. Care Medicine, NorthShore University HealthSystem, 2650 Ridge Pleural effusion may accompany the IFN-induced capil- Avenue, Evanston, IL 60201; Telephone: 847-570-2714; Fax: 847- 2 733-5109; E-mail: [email protected] Received 19 July 2008; lary leak syndrome. revision received 16 October 2008; accepted 17 October 2008. There have been only 2 other cases of pleural effusion during treatment with IFN alpha described to date.3,4 Takeda et al.3 described a 54-year-old male who was acci- dentally detected to have a moderate-sized right pleural References effusion on magnetic resonance imaging (MRI) of the abdo- 1. Foucher P, Camus P. Groupe d’Etudes de la Pathologie Pulmonaire Iatro- men, 14 days after therapy with recombinant IFN alpha was ge`ne (GEPPI). Pneumotox Online. The drug-induced lung diseases. Avail- able at: http://www.pneumotox.com. Accessed February 2009. initiated. The pleural fluid was a lymphocyte-predominant 2. Carson JJ, Gold LH, Barton AB, et al. Fatality and interferon alpha for ma- exudate and resolved approximately 4 months after discon- lignant melanoma. Lancet. 1998;352(9138):1443–1444. 4 tinuation of IFN treatment. Tsushima et al. reported bilat- 3. Takeda A, Ikegame K, Kimura Y, et al. Pleural effusion during interferon eral pleural effusions and ground-glass opacities in a patient treatment for chronic hepatitis C. Hepatogastroenterology. 2000;47(35): treated with IFN for metastatic renal cell cancer that 1431–1435. 4. Tsushima K, Yamaguchi S, Furihata K, et al. A case of renal cell carcinoma resolved following a course of steroids. complicated with interstitial pneumonitis, complete A-V block and pleural IFN-related pulmonary toxicity has been reported to typi- effusion during interferon-alpha therapy. Nihon Kokyuki Gakkai Zasshi. cally develop between 2 and 16 weeks of treatment. Our 2001;39:893–898. patient had a delayed onset of symptoms at 30 weeks and 5. Yamaguchi S, Kobo K, Fujimoto K, et al. Analysis of bronchoalveolar la- progressed on to develop left pleural effusion and pulmo- vage fluid of patients with chronic hepatitis c before and after treatment with interferon alpha. Thorax. 1997;52:33–37. nary infiltrates by the time she finished 44 weeks of treat- 6. Midturi J, Sierra-Hoffman M, Hurley D, et al. Spectrum of pulmonary tox- ment. We ruled out infectious, malignant, cardiac, and auto- icity associated with the use of interferon therapy for hepatitis C: case immune causes, which often present in a similar fashion. report and review of the literature. Clin Infect Dis. 2004;39:1724–1729.

2009 Society of Hospital Medicine DOI 10.1002/jhm.452 Published online in wiley InterScience (www.interscience.wiley.com).

E46 Journal of Hospital Medicine Vol 4 No 7 September 2009